phosphocreatine and Cardiomyopathies

Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder characterized by progressive and irreversible loss of muscular function. As muscular disease progresses, the repair mechanisms cannot compensate for cellular damage, leading inevitably to necrosis and progressive replacement by fibrous and fatty tissue. Cardiomyopathy and respiratory failure are the main causes of death in DMD. In addition to the well-described muscle and heart disease, cognitive dysfunction affects around 30% of DMD boys. Myocardial fibrosis, assessed by late gadolinium enhancement (LGE), using cardiovascular magnetic resonance imaging (CMR), is an early marker of heart involvement in both DMD patients and female carriers. In parallel, brain MRI identifies smaller total brain volume, smaller grey matter volume, lower white matter fractional anisotropy and higher white matter radial diffusivity in DMD patients. The in vivo brain evaluation of mdx mice, a surrogate animal model of DMD, showed an increased inorganic phosphate (P(i))/phosphocreatine (PCr) and pH. In this paper, we propose a holistic approach using techniques of magnetic resonance imaging, spectroscopy and diffusion tensor imaging as a tool to create a "heart and brain imaging map" in DMD patients that could potentially facilitate the patients' risk stratification and also future research studies in the field.

Topics: Animals; Anisotropy; Brain; Cardiomyopathies; Cognitive Dysfunction; Diffusion Tensor Imaging; Disease Models, Animal; Fibrosis; Gray Matter; Heart; Heterozygote; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred mdx; Muscular Dystrophy, Duchenne; Myocardium; Organ Size; Phosphates; Phosphocreatine; White Matter

The 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen is widely used in the management of breast cancer. The common cardiotoxic effects of doxorubicin include congestive heart failure and left ventricular dysfunction, and those of cyclophosphamide include pericarditis, myocarditis, and congestive heart failure. It has been postulated that cardiotoxicity of 5-fluorouracil presents as coronary artery diseases (eg, angina). Cardiomyopathy is a common outcome following treatment with the FAC regimen. We report on a 52-year-old woman with cardiomyopathy following chemotherapy and radiation therapy. The patient did not respond well to b-blockers and angiotensin-converting enzyme inhibitors. After the addition of exogenous phosphocreatine, the patient's cardiac condition improved significantly.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiomyopathies; Cardiotoxicity; Cyclophosphamide; Doxorubicin; Electrocardiography; Female; Fluorouracil; Humans; Middle Aged; Phosphocreatine; Tomography, X-Ray Computed; Treatment Outcome

To evaluate the effects of creatine phosphate (CP) in the treatment of myocardial damage following neonatal asphyxia.. Medical databases were searched for a systematic literature review and meta-analysis of randomized and quasi-randomized trials on the treatment of myocardial damage with CP following neonatal asphyxia. The data was analyzed using Review Manager 5.1.. Six trials involving 400 patients (CP treatment/control: 202/198) were included in the survey. The meta-analysis indicated that CP treatment for 7 days decreased serum myocardial enzyme levels (CK, CK-MB, LDH, HBDH and cTnI levels). Both the total effective rate (RR: 1.29; 95% CI: 1.12, 1.48) and the significantly effective rate (RR: 1.78; 95% CI: 1.32, 2.41) in the CP treatment group were significantly higher than in the control group. CP treatment reduced the hospitalization period by 4.07 days compared with the control group (95% CI: -5.25, -2.89).. CP treatment appears to be more effective than routine treatment alone for myocardial damage following neonatal asphyxia. It appears to be safe and it can both decrease serum myocardial enzyme levels and shorten the period of hospitalization. However, as the evidence obtained in this study is not robust due to the poor quality of current studies, further studies of high-quality, large-scale trails are needed.

Topics: Asphyxia Neonatorum; Cardiomyopathies; Cardiotonic Agents; Humans; Infant, Newborn; Length of Stay; Myocytes, Cardiac; Phosphocreatine; Randomized Controlled Trials as Topic

Topics: Animals; Cardiomyopathies; Cell Nucleus; Cricetinae; Cytoplasm; DNA; Dogs; Golgi Apparatus; Heart Failure; Humans; Hypertrophy; Hypoxia; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Phosphocreatine; Protein Biosynthesis; Rabbits; Rats; RNA; Sarcolemma

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

Topics: Adenosine Triphosphate; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cardiomyopathies; Carnitine; Constriction; Echocardiography; Genetic Predisposition to Disease; Heterozygote; Hypertension; Lung; Male; Mice; Mice, Mutant Strains; Mutation; Myocardium; Organ Size; Organic Cation Transport Proteins; Phosphocreatine; RNA, Messenger; Solute Carrier Family 22 Member 5

Long-chain fatty acids (FAs) are the predominant energy substrate utilized by the adult heart. The heart can utilize unesterified FA bound to albumin or FA obtained from lipolysis of lipoprotein-bound triglyceride (TG). We used heart-specific lipoprotein lipase knock-out mice (hLpL0) to test whether these two sources of FA are interchangeable and necessary for optimal heart function. Hearts unable to obtain FA from lipoprotein TG were able to compensate by increasing glucose uptake, glycolysis, and glucose oxidation. HLpL0 hearts had decreased expression of pyruvate dehydrogenase kinase 4 and increased cardiomyocyte expression of glucose transporter 4. Conversely, FA oxidation rates were reduced in isolated perfused hLpL0 hearts. Following abdominal aortic constriction expression levels of genes regulating FA and glucose metabolism were acutely up-regulated in control and hLpL0 mice, yet all hLpL0 mice died within 48 h of abdominal aortic constriction. Older hLpL0 mice developed cardiac dysfunction characterized by decreased fractional shortening and interstitial and perivascular fibrosis. HLpL0 hearts had increased expression of several genes associated with transforming growth factor-beta signaling. Thus, long term reduction of lipoprotein FA uptake is associated with impaired cardiac function despite a compensatory increase in glucose utilization.

Topics: Adenosine Triphosphate; Animals; Blood Glucose; Carbon Radioisotopes; Cardiomyopathies; Cholesterol; Echocardiography; Fasting; Fatty Acids; Female; Gene Expression; Glucose; Glucose Transporter Type 4; Glycolysis; Kinetics; Lipoprotein Lipase; Lipoproteins, VLDL; Male; Mice; Mice, Knockout; Myocardium; Myocytes, Cardiac; Oxidation-Reduction; Phosphocreatine; Protein Kinases; Triglycerides

This study evaluated myocardial function in relation to high-energy phosphate (HEP) metabolism in asymptomatic patients with uncomplicated type 2 diabetes mellitus using magnetic resonance (MR) techniques.. Myocardial dysfunction may occur in patients with type 2 diabetes mellitus in the absence of coronary artery disease or left ventricular (LV) hypertrophy. The mechanisms underlying this diabetic cardiomyopathy are largely unknown, but may involve altered myocardial energy metabolism.. We assessed myocardial systolic and diastolic function and HEP metabolism in 12 asymptomatic normotensive male patients with recently diagnosed, well-controlled type 2 diabetes and 12 controls, using MR imaging and phosphorus-31-nuclear MR spectroscopy (31P-MRS) on a 1.5 T clinical scanner; 31P-MR spectra were quantified, and myocardial HEP metabolism was expressed as phosphocreatine to adenosine-triphosphate (PCr/ATP) ratio.. No differences were found in LV mass and systolic function between patients and controls. However, early (E) acceleration peak, deceleration peak, peak filling rate, and transmitral early-to-late diastolic peak flow (E/A) ratio, all indexes of diastolic function, were significantly decreased in patients compared with controls (p < 0.02). In addition, myocardial PCr/ATP in patients was significantly lower than in controls (1.47 vs. 1.88, p < 0.01). Inverse associations were found between myocardial PCr/ATP and E acceleration peak, E deceleration peak, and E peak filling rate (all, p < 0.05).. These results indicate that altered myocardial energy metabolism may contribute to LV diastolic functional changes in patients with recently diagnosed, well-controlled and uncomplicated type 2 diabetes.

Topics: Adenosine Triphosphate; Aged; Analysis of Variance; Blood Glucose; Cardiomyopathies; Case-Control Studies; Diabetes Mellitus, Type 2; Diastole; Disease Progression; Energy Metabolism; Fatty Acids, Nonesterified; Glycated Hemoglobin; Hemodynamics; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phosphocreatine; Phosphorus Isotopes; Risk Factors; Systole; Ventricular Function, Left

Reports have attributed cardiac failure during acute models of endotoxemia to a lack of high-energy phosphates. This study was undertaken to investigate whether creatine (Cr) administered during perfusion could enhance myocardial protection and improve recovery of cardiac function in a rat model of endotoxemia.. Acute endotoxemia was induced in rats by a bolus injection of Escherichia coli endotoxin (LPS: 4 mg/kg, ip) while control rats were injected with an equal volume of 0.9% normal saline. To assess the adequacy of energy metabolism, freeze-clamped hearts were obtained from animals to study the concentrations of endogenous ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), and intracellular pH by (31)P-cryomagnetic resonance spectroscopy. In a separate experiment, isolated hearts were perfused via a Langendorff column with Krebs-Henseleit buffer containing different concentrations of creatine monohydrate (1, 3, or 10 mM). Cardiac performance was evaluated via a paced (300 bpm) isovolumetric balloon preparation. Measurements of cardiac function including left ventricular developed pressure (LVDP), the maximum rates of ventricular pressure rise (LV +dP/dt) and fall (LV -dP/dt), and coronary flow were made for both LPS and saline-treated animals.. High-energy phosphate ratios of PCr/ATP and PCr/P(i) in hearts declined significantly at 4 h after endotoxin treatment. As anticipated, LVDP and LV +dP/dt(max) at a given preload and heart rate were significantly (P < 0.05) lower at 4 h when measured at the same time point. The functional recovery of these parameters was not improved by the addition of creatine monohydrate to the perfusion buffer. Creatine produced a significant (P < 0.05) negative inotropic effect in hearts from saline-treated animals. The LVDP was reduced by 30% at the lowest concentration and by 50% at the highest concentration of creatine monohydrate. Furthermore, creatine significantly (P < 0.05) reduced LV -dP/dt(max) in both saline and LPS-treated rats. These data demonstrate that exogenous creatine does not contribute to myocardial preservation in endotoxemia.. Energy stores in the rat heart decline early in endotoxemia accompanied by reduced myocardial performance, suggesting that the ability of the heart to perform mechanical work is impaired. Cardiac dysfunction in an acute model of endotoxemia was not improved with exogenous creatine during perfusion. Creatine's effects were primarily lusitropic by delaying the onset of myocardial relaxation in all hearts. The deleterious effects of exogenous creatine monohydrate in normal hearts should be examined in future experimental studies.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Creatine; Disease Models, Animal; Endotoxemia; In Vitro Techniques; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Male; Myocardium; Phosphocreatine; Rats; Rats, Sprague-Dawley; Specific Pathogen-Free Organisms; Ventricular Pressure

Ruptured abdominal aortic aneurysm (RAAA) repair, a combination of hemorrhagic shock and lower-torso ischemia, is associated with a 50-70% mortality. Myocardial dysfunction may contribute to the high rate of mortality after aneurysm repair. We attempted to determine whether RAAA repair results in cardiac dysfunction mediated by tumor necrosis factor-alpha (TNF-alpha). We modeled aortic rupture and repair in the rat by inducing hemorrhagic shock to a mean blood pressure of 50 mmHg for 1 h, followed by supramesenteric clamping of the aorta for 45 min. After 90 min of reperfusion, cardiac contractile function was assessed with a Langendorff preparation. Myocardial TNF-alpha, ATP and creatine phosphate (CP) levels, and markers of oxidant stress (F(2)-isoprostanes) were measured. Cardiac function in the combined shock and clamp rats was significantly depressed compared with sham-operated control rats but was similar to that noted in animals subjected to shock alone. Myocardial TNF-alpha concentrations increased 10-fold in the combined shock and clamp rats compared with sham rats, although there was no difference in myocardial ATP, CP, or F(2)-isoprostanes. TNF-alpha neutralization improved cardiac function by 50% in the combined shock and clamp rats. Hemorrhagic shock is the primary insult inducing cardiac dysfunction in this model of RAAA repair. An improvement in cardiac contractile function after immunoneutralization of TNF-alpha indicates that TNF-alpha mediates a significant portion of the myocardial dysfunction in this model.

Topics: Adenosine Triphosphate; Aneurysm, Ruptured; Animals; Antibodies; Aorta; Aortic Aneurysm, Abdominal; Cardiomyopathies; Constriction; Ischemia; Male; Myocardium; Peroxidase; Phosphocreatine; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Our aim was to measure the cardiac phosphocreatine to adenosine triphosphate ratio (PCr/ATP) noninvasively in patients and carriers of Xp21 muscular dystrophy and to correlate the results with left ventricular (LV) function as measured by echocardiography.. Duchenne and Becker muscular dystrophy (the Xp21 dystrophies) are associated with the absence or altered expression of dystrophin in cardiac and skeletal muscles. They are frequently complicated by cardiac hypertrophy and dilated cardiomyopathy. The main role of dystrophin is believed to be structural, but it may also be involved in signaling processes. Defects in energy metabolism have been found in skeletal muscle in patients with Xp21 muscular dystrophy. We therefore hypothesized that a defect in energy metabolism may be part of the mechanism leading to the cardiomyopathy of Xp21 muscular dystrophy.. Thirteen men with Becker muscular dystrophy, 10 female carriers and 23 control subjects were studied using phosphorus-31 magnetic resonance spectroscopy and echocardiography.. The PCr/ATP was significantly reduced in patients (1.55+/-0.37) and carriers (1.37+/-0.25) as compared with control subjects (2.44+/-0.33; p<0.0001 for both groups). The PCr/ATP did not correlate with LV ejection fraction or mass index.. Altered expression of dystrophin leads to a reduction in the PCr/ATP. Since this reduction did not correlate with indexes of left ventricular function, this raises the possibility of a direct link between altered dystrophin expression and the development of cardiomyopathy in such patients.

Topics: Adenosine Triphosphate; Adult; Cardiomyopathies; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscular Dystrophy, Duchenne; Myocardium; Phosphocreatine

A test drug (Lipistat) comprising of equal-proportions of extracts of Terminalia arjuna, Inula racemosa Hook, latex of Commiphora mukul, in three different doses (225 mg/kg; 350 mg/kg; 450 mg/kg) were administered orally daily for 6 days a week for 60 days in rats. Thereafter, the rats were subjected to isoproterenol (ISO) induced (85 mg/kg, s.c. for 2 days) myocardial necrosis. Gross and microscopic examinations (histopathology) were done along with estimations of myocardial tissue high energy phosphates (HEP) stores and lactate content. Gross examination showed significant (P < 0.05) cardioprotection in Lipistat treated animals. On microscopic examination no statistically significant reduction in myocardial damage by 350 and 450 mg/kg of Lipistat were observed although loss of myocardial HEP stores and accumulation of lactate were significantly prevented. The results of the present study suggest the potential usefulness of Lipistat in the prevention of ischemic heart disease.

Topics: Adenosine Triphosphate; Adrenergic beta-Agonists; Animals; Cardiomyopathies; Fat Necrosis; Female; Hypolipidemic Agents; Isoproterenol; Lactic Acid; Male; Myocardium; Myofibrils; Phosphocreatine; Phytotherapy; Rats; Rats, Wistar

Metabolic differences between cardiomyopathic hamsters (CMHs), as they progress through various physiologic phases before reaching end-stage heart failure (HF), and healthy hamsters (HHs) are often difficult to demonstrate. We suggest that metabolic differences, magnified by application of chronic stress (S: cold immobilization 2 hr/day for 5 days) followed by acute stress (AS: 55 min global ischemia /30 min reperfusion), can be used to characterize different stages in this cardiomyopathic process. High performance liquid chromatography (HPLC) and 31P NMR methods were used to monitor the effects of acute stress applied to nonstressed (NS) and previously stressed CMHs (NS-2.5-month NS-5-month; S-2.5-month, S-5-month) and HHs (NS-HH, S-HH). Cardiac tissue extracts from nonstressed and stressed hamsters were analyzed for ATP and PCr at baseline and after completion of ischemia/reperfusion (AS) using HPLC. In nonstressed hamsters, ATP and PCr were 12% lower in CMHs (both NS-2.5- and NS-5-month) than in NS-HHs. After exposure to stress, ATP was 26% lower in CMHs (S-2.5- and S-5-month) compared to S-HHs, whereas there were minimal differences in PCr between the groups. 31P NMR monitoring of metabolism in the perfused beating heart during application of acute stress produced similar changes (%) in ATP and PCr in all groups (NS and S), whereas Pi increase was less in NS-5-month (118%) compared to NS-2.5-month (179%) and NS-HHs (306.8%), P < 0.05; and in S-5-month (148%) compared to S-2.5-month (216%) and S-HHs (222%). The changes in myocardial pH were inversely related to changes in Pi: NS-5-month (-13.5%); NS-2.5-month (-9.7%); NS-HH (-17.7%). pH changes in stressed cardiomyopathic hamsters were similar to those of S-HHs. The postischemic recovery of ATP and Pi return closer to baseline values in cardiomyopathic hamsters (both NS and S) compared to healthy hamsters. The data suggest that cardiomyopathic hamsters have baseline metabolic abnormalities, and their responses to chronic cold immobilization stress, acute ischemia, and chronic cold immobilization stress plus acute ischemia are different from those in HHs. These responses may help to characterize specific stages of disease.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Chromatography, High Pressure Liquid; Cricetinae; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardial Reperfusion Injury; Myocardium; Perfusion; Phosphocreatine; Stress, Physiological

One feature of the diabetic cardiomyopathy is the appearance of contractile dysfunction as the workload increases. We hypothesized that this resulted from an impaired creatine kinase/phosphocreatine system and therefore examined the creatine kinase kinetics at both low and high workloads. Creatine kinase flux (by 31P nuclear magnetic resonance saturation transfer method), cardiac performance, and oxygen consumption were measured in control and streptozotocin-induced diabetic rat hearts. Creatine kinase flux was inhibited by iodoacetamide in control hearts to confirm the role of the creatine kinase/phosphocreatine system in cardiac performance. In diabetic hearts, 1) the contractile dysfunction became apparent only at high workloads, 2) the ATP synthesis rate was not significantly different from control hearts, 3) the creatine kinase flux was reduced by 30.8% (257.5 +/- 7.7 mumol.g wet wt-1.min-1 in control vs. 178.3 +/- 9.4 in diabetes, P < 0.001), and 4) the creatine kinase flux did not increase as the workload increased. In control hearts, 5) iodoacetamide inhibited the creatine kinase flux to the same degree as that in diabetic hearts, and 6) the contractile dysfunction was not as severe as that observed in diabetic hearts. These results suggest that the impaired creatine kinase/phosphocreatine system is, at least in part, responsible for the contractile dysfunction in the diabetic cardiomyopathy.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Creatine Kinase; Diabetes Mellitus, Experimental; Heart; In Vitro Techniques; Iodoacetates; Iodoacetic Acid; Kinetics; Magnetic Resonance Spectroscopy; Male; Myocardium; Perfusion; Phosphates; Phosphocreatine; Rats; Rats, Sprague-Dawley; Reference Values; Regression Analysis; Ventricular Function, Left

The aim of the present experimental study in the rat heart was to assess cardiac performance and metabolism in mild diabetes of 2 months' duration (postprandial blood sugar levels of 307 +/- 101 mg/dl and nearly normal fasting blood glucose of 102 +/- 40 mg/dl) using the working rat heart model at physiological workload with a perfusion time of 60 min. We also compared the effect of two forms of therapy for diabetes, islet transplantation and insulin therapy (s.c.), after 2 months. A 36% reduction in glucose utilization is metabolically characteristic for the diabetic heart, mainly caused by a 55% reduced glucose uptake (P < 0.001), but also by a nearly twofold increased lactate and pyruvate production (P < 0.001). This reduced carbohydrate metabolism is accompanied by a 37% reduction of oxygen uptake (P < 0.001) as well as a significant reduction in myocardial ATP and CP levels (P < 0.001), resulting in a significantly reduced cardiac output (P < 0.001). Moreover, the balance of energy reveals that the diabetic heart obtains 46% of its energy requirements for 1 h from endogenous glycogen, whereas the control heart obtains 91% of its energy needs (i.e. preferentially) from exogenous glucose (only 9% from endogenous glycogen). Both investigated therapeutic interventions led to a complete reversibility of the hemodynamic and metabolic alterations, indicating that the cause of diabetic cardiomyopathy in this model of mild and short-term diabetes is due to a defect in cardiac carbohydrate metabolism, which is correctable by insulin administration.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Cardiac Output; Cardiomyopathies; Diabetes Mellitus, Experimental; Energy Metabolism; Glucose; Glycogen; In Vitro Techniques; Insulin; Islets of Langerhans Transplantation; Lactates; Male; Myocardium; Oxygen Consumption; Phosphocreatine; Pyruvates; Rats; Rats, Inbred Lew; Triglycerides; Ventricular Dysfunction, Left

Topics: Adenosine Triphosphate; Animals; Blood Glucose; Cardiac Output; Cardiomyopathies; Diabetes Mellitus, Experimental; Heart; Heart Rate; Hemodynamics; Insulin; Islets of Langerhans Transplantation; Myocardium; Organ Size; Phosphocreatine; Rats; Rats, Inbred Lew; Time Factors

In order to study the metabolic consequences of myocardial stunning, repeated coronary occlusions were performed in dogs. The production of CO2, adenosine triphosphate (ATP), phosphocreatine (PCr), and inorganic phosphate (Pi) by myocardial cells was assessed, along with extracellular and intracellular pH. Our results indicate that regional coronary artery occlusion reduces the ability of the myocardium to produce H+ and CO2 and to replenish ATP post ischemia. These alterations, then, represent the hallmark of metabolic viability during periods of ischemic insult. Decreases in PCr and Pi were completely eliminated during reperfusion and, therefore, are ot reflective of myocardial stunning. When normothermic cardiopulmonary bypass (CPB) is instituted and the coronary artery is occluded three times with reperfusion between each occlusion, alterations in myocardial H+ and high energy phosphates are identical to those observed using only repetitive coronary occlusion. Systemic hypothermia during CPB does not protect against myocardial stunning; however, it is anticipated that interventions that prevent the reduction in H+ and ATP levels may overcome the effects of myocardial stunning that occur during cardiac surgery.

Topics: Adenosine Triphosphate; Animals; Carbon Dioxide; Cardiomyopathies; Cardiopulmonary Bypass; Dogs; Hypothermia, Induced; Myocardial Contraction; Myocardial Reperfusion; Myocardium; Phosphates; Phosphocreatine

Background. It might be possible to estimate the metabolic derangement of cardiac muscle by topical nuclear magnetic resonance spectroscopy (MRS) in vivo without killing the animal. Methods and Results. By use of topical 1H- and 31P-MRS focused on the heart of Syrian hamsters with or without cardiomyopathy (CM; BIO 14.6 strain), the chemical constituents were measured in vivo nondestructively and repetitively at several stages of development of CM. A phantom experiment and two-dimensional plot of chain methylenes (CH2) of lipid/water ratio by 1H-MRS versus creatine phosphate (CP)/[beta-P]ATP ratio by 31P-MRS indicated that signal cross talk from the adjacent organs was negligible. Even before the onset of clinical or pathological manifestation of CM (7 weeks after birth), CH2/water ratio by 1H-MRS was lower in the CM group (7.3 +/- 0.7%) than in control (11.8 +/- 2.0%, p less than 0.05), and it decreased further at the hypertrophic stage (17 weeks, 4.1 +/- 0.7%, p less than 0.05) and the congestive stage (27 weeks, 4.3 +/- 0.9%, p less than 0.05). In contrast, the CP/[beta-P]ATP ratio by 31P-MRS started to decrease at the hypertrophic stage (1.90 +/- 0.18 versus 2.52 +/- 0.24, p less than 0.05) and decreased further at the congestive stage to 1.53 +/- 0.18 (p less than 0.01). These in vivo MRS data were confirmed by both biochemical assay and in vitro MRS analysis in heavy water after the animals were killed. Conclusions. A combination of topical 1H-MRS and 31P-MRS in vivo is promising for the noninvasive and sensitive assessment of cardiac muscle metabolism. Comparison of these MRS studies and biochemical analysis suggested not only the modification of water, lipid, CP, or ATP contents but also the reduction of flexibility or fluidity of lipids in cardiomyopathic heart.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Cricetinae; Magnetic Resonance Spectroscopy; Male; Mesocricetus; Myocardium; Phosphocreatine; Phosphorus; Protons

We have demonstrated that food restriction that is associated with weight loss can produce a type of cardiac dysfunction similar to that produced by diabetes. As in diabetic atria, the food-restricted atria had a 2-fold increase in contraction force, rate of force development, and rate of force decline compared with controls. Both food-restricted and diabetic atria could tolerate anoxia better than controls. The contractile function of the whole perfused heart from the food-restricted rat was reduced, as in the case of the diabetic heart. As the left ventricular volume was increased, the left ventricular developed pressure and the rate of rise and fall in pressure were significantly reduced in both food-restricted and diabetic hearts, compared with those of age- and weight-matched controls. The positive inotropic responses of atria and whole perfused heart to increasing concentrations of extracellular calcium were similarly altered in food-restricted and diabetic hearts. The possible molecular mechanisms of these findings and some of the differences observed between food-restricted and diabetic hearts are discussed.

Topics: Adenosine Triphosphate; Animals; Blood Glucose; Calcium; Cardiomyopathies; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diet, Reducing; Insulin; Male; Myocardial Contraction; Phosphocreatine; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

Nuclear magnetic resonance spectroscopy (MRS) is a new technique for the evaluation of myocardial metabolism. Recently, localized MRS has been clinically available to measure by a non-invasive method the relative concentrations of the high-energy phosphate metabolites in the myocardium. We performed ECG gated P-31 MRS using ISIS (image-selected in vivo spectroscopy) in 15 normal volunteers, 12 patients with hypertrophic cardiomyopathy, 12 with left ventricular hypertrophy, 6 with dilated cardiomyopathy and 11 with specific heart muscle disease. Myocardial peak height ratios of PCr/gamma-ATP, Pi/gamma-ATP and PCr/Pi were measured. Myocardial P-31 MRS demonstrated a significant decrease in the ratio PCr/ATP in patients with hypertrophic cardiomyopathy and specific heart muscle disease as compared with normal subjects, indicating myocardial metabolic disturbance in these patients. The ratio of PCr/ATP in patients with dilated cardiomyopathy did not differ significantly from that of normal subjects. However, exercise MRS revealed a marked decrease of PCr peak in an asymptomatic patient with dilated cardiomyopathy, which may indicate a latent metabolic disturbance in the myocardium of dilated cardiomyopathy.

Topics: Adenosine Triphosphate; Adult; Cardiomyopathies; Electrocardiography; Humans; Magnetic Resonance Spectroscopy; Middle Aged; Myocardium; Organophosphates; Phosphocreatine; Phosphorus

The aim of this study was to evaluate the ability of propionyl-L-carnitine to prevent cardiac damage induced by erucic acid. Rats were fed for 10 days with normal or 10% erucic acid-enriched diets with or without propionyl-L-carnitine intraperitoneally injected, (1 mM/kg daily, for 10 days). The erucic acid diet produced increases in triglycerides (from 5.6 to 12.4 mg/gww, P less than 0.01), and free fatty acids (from 2.0 to 5.1 mg/gww, P less than 0.01), but no changes in phospholipids. When the hearts were perfused aerobically with an isovolumic preparation there was no difference in mechanical activity. On the contrary, when pressure-volume curves were determined, the pressure developed by hearts from the erucic acid-treated rats were reduced. Independent of diet, propionyl-L-carnitine treatment always produced positive inotropy. This was concomitant with improved mitochondrial respiration (RCI 5.1 vs 9.3, P less than 0.01), higher tissue ATP content (10.3 vs 18.4 mumol/gdw P less than 0.01) and reduction of triglycerides (12.4 vs 8.0 mg/gww, P less than 0.01). These data suggest that propionyl-L-carnitine, when given chronically, is able to prevent erucic acid-induced cardiotoxicity, probably by reducing triglyceride accumulation and improving energy metabolism.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Carnitine; Erucic Acids; Heart; Lipid Metabolism; Male; Mitochondria, Heart; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains

Chemically skinned (by treatment with saponin, 40 micrograms/ml) isolated cardiomyocytes were used to study the intracellular diffusion of ADP and creatine (Cr). Stimulation of respiration was studied in these cardiomyocytes without intact sarcolemma and in isolated heart mitochondrial by addition of ADP and Cr in the presence of 0.2 mM ATP (via mitochondrial creatine kinase reaction: Cr + MgATP = MgADP + PCr). The Michaelis constant (Km) for Cr was similar in both cases, 5.67 +/- 0.11 (SD) mM in skinned myocytes and 6.9 +/- 0.2 mM in mitochondria, showing that there is no significant restriction to the diffusion of this substrate. However, the apparent Km for external ADP increased from 17.6 +/- 1.0 microM for mitochondria to 250 +/- 38 microM for skinned cardiomyocytes, showing decreased diffusivity of ADP as a result of binding to cellular structures. In the presence of 25 mM Cr, the Km for ADP for myocytes decreased to 35.6 +/- 5.6 microM due to the coupling of the creatine kinase and oxidative phosphorylation reactions. Provision of substrate for the creatine kinase reaction amplified the weak ADP signal in the regulation of respiration. The activity of the mitochondrial creatine kinase was decreased by a factor of two in cardiomyopathic hamsters and human hearts and was associated with a twofold decrease in creatine-stimulated respiration. These data show a potentially key role of mitochondrial creatine kinase in the regulation of cellular respiration and the possible importance of changes in its activity for the functional disturbances of the cardiomyopathic heart.

Topics: Adenosine Diphosphate; Animals; Biological Transport; Cardiomyopathies; Creatine Kinase; Diffusion; Energy Metabolism; Microscopy, Electron, Scanning; Mitochondria, Heart; Myocardium; Permeability; Phosphocreatine; Saponins; Sarcolemma

A recirculating, retrograde heart perfusion according to Langendorff is described as a method for the evaluation of cardiomyopathy as an untoward side effect of a high lipid diet (addition of 10% and 25% corn oil to rat maintenance feed) in female rats. The use of glucose (5 mM) or palmitate (0.5 mM/0.1 mM BSA) as substrates during a 2-h perfusion period, and their effects on heart metabolism of control-, LL- and HL-diet fed animals were evaluated. Substrate uptake, LDH release and adenine nucleotides, creatine phosphate, creatine, lactate, pyruvate, glucose-6-phosphate, glycogen, triglyceride and phospholipid content were determined in heart tissue.

Topics: Animals; Cardiomyopathies; Creatine Kinase; Dietary Fats; Energy Metabolism; Female; Glycogen; L-Lactate Dehydrogenase; Myocardium; Perfusion; Phosphocreatine; Pyruvates; Pyruvic Acid; Rats

Previous studies suggested that one possible mechanism of doxorubicin (DXR)-induced cardiomyopathy involves the depletion of high-energy phosphate stores. In this study, we used 31P nuclear magnetic resonance to assess the high-energy phosphate content in Langendorff perfused rat hearts. Hearts were perfused in normoxic conditions (spontaneous flow) or in partially hypoxic conditions obtained by perfusing at 50% of the spontaneous flow. DXR was used at the subtoxic conditions of 50 mg/l for 15 min and at the cardiotoxic concentration of 100 mg/l for 60 min. Left ventricular pressure (dP/dt), heart rate, myocardial ATP and PCr levels and PCr/ATP ratio were measured. We found that, in normoxic conditions, DXR (50 mg/l, 15 min) does not impair cellular high-energy phosphate metabolism. However, in mild hypoxic conditions, DXR induces a significant decrease in PCr/ATP ratio, due to a decrease in PCr and to a simultaneous increase in ATP. Similar results are obtained after 60 min perfusion with the cardiotoxic dose of DXR. This study suggests that hypoxia may represent a risk factor for the development of DXR-induced acute cardiotoxicity.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Doxorubicin; Heart; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardium; Oxygen; Phosphocreatine; Rats; Rats, Inbred Strains; Risk Factors

Functional states of cardiac contractile apparatus and mitochondria were studied in hereditary cardiomyopathic hamsters (CHF 146) and control golden hamsters using cardiac fibers skinned by two different techniques. The Triton X-100 skinned fibers obtained from diseased animals of 175 to 200 days old, or from control animals, demonstrated the same resting and maximal Ca-activated tensions, the same stiffness, the same rate of tension recovery after quick stretch; the fibers from cardiomyopathic animals differed only by a slightly increased calcium sensitivity. Functional activity of myofibrillar creatine kinase in cardiomyopathy was decreased as indicated by a smaller shift in the pMgATP/rigor tension curve to lower [MgATP] in the presence of phosphocreatine and by a slower rate of the tension recovery after quick stretch in the presence of phosphocreatine and ADP (without ATP). The saponin-skinned fibers allow evaluation of the respiration properties of the total tissue mitochondria. Data obtained in the preparations isolated from diseased animals of two ages (75 to 100 and 175 to 200 days) showed that the ratio of maximal ADP-stimulated respiration rate to the respiration rate in the absence of ADP (an analog of respiration control index) was unchanged in myopathy as compared with age-matched controls. However stimulation of respiration after an addition of creatine at submaximal ADP concentration was observed to be respectively 1.45 times and 3.5 times less in the preparations from younger and older myopathic animals as compared with their respective controls, thus indicating the impairment of functional coupling between mitochondrial creatine kinase reaction and oxidative phosphorylation. These results suggest that hereditary cardiomyopathy is associated with alterations in myocardial creatine kinase system, while myofilaments and mitochondria preserve their basic functional properties.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Cardiomyopathies; Creatine Kinase; Cricetinae; Heart; Heart Ventricles; Mesocricetus; Mitochondria, Heart; Myocardial Contraction; Myocardium; Myofibrils; Oxygen Consumption; Phosphocreatine

Isolated hearts from normal and cardiomyopathic hamsters (160 to 180 days of age) were perfused through the aorta and assessed by echocardiographic and 31P-NMR (nuclear magnetic resonance) techniques. A decreased left ventricular systolic pressure in cardiomyopathic hamsters was associated with diminished cardiac size and left ventricular wall thickness. However, the ratio of inner/outer cross-sectional area and estimated left ventricular volume at any given left ventricular weight was significantly higher, indicating relative left ventricular chamber enlargement in cardiomyopathic hamsters. Left ventricular volumes were increased with an intraventricular balloon. Gradual inflation of the balloon resulted in increments of left ventricular systolic and developed stress that rose to the same values in both groups. At this point, the normalized stress-strain relationship was approximately two times steeper for cardiomyopathic hamsters, while at lower strain values the diastolic stress in cardiomyopathic hamsters was less than in controls, possibly due to cardiac dilatation. Almost the same degree of dilatation was induced in control hearts by the acute addition of 1% alcohol, but it was not followed by increased diastolic stiffness. Examination of hearts by 31P-NMR techniques revealed a decreased phosphocreatine/inorganic phosphate (PCr/Pi) ratio in the cardiomyopathic hamsters that progressed further with balloon inflation and was associated with a relative fall in PCr and adenosine triphosphate (ATP) content. Results suggest increased diastolic stiffness in cardiomyopathic hamsters, which was not seen in acute cardiac depression with alcohol. Diastolic volume overload with increased wall stress is probably the major factor contributing to increased diastolic stiffness early in the cardiomyopathy.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiomyopathies; Cricetinae; Disease Models, Animal; Echocardiography; Ethanol; Heart; Heart Ventricles; Mesocricetus; Myocardium; Phosphates; Phosphocreatine

31P magnetic resonance spectroscopy, using surface coils placed on perfused or surgically exposed animal hearts, shows that unequivocal changes in phosphocreatine (PCr) and adenosine triphosphate (ATP) occur during interventions, such as ischemia. Similar measurements seem warranted in man. We have used a modification of the rotating-frame imaging technique to measure PCr-to-ATP ratio non-invasively in human heart. The subject lay prone on a double-surface coil probe with the apex and the anterior surface of the heart covered by the coil in a 1.9 T magnet. 31P spectra were obtained from slices of tissue approximately 6 cm in diameter and 2 cm in thickness. Though skeletal and cardiac muscle contain similar phosphorus metabolites, animal studies show that the ratio in the two are different. We argued that the ratio should start high (skeletal muscle) and plateau at a low value representing cardiac muscle. Using this criterion, which makes no assumption on what the ratio is in heart muscle, the PCr:ATP in six normal subjects was 1.55 +/- 0.2. This protocol has been used in a preliminary study in patients with cardiomyopathies.

Topics: Adenosine Triphosphate; Cardiomyopathies; Humans; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus; Reference Values

In vivo 31P-NMR was used to measure the effects of the anti-tumor drug adriamycin on the energy metabolism of rat heart. The exclusive acquisition of NMR signal from cardiac muscle was assured by positioning a solenoidal radio-frequency NMR coil around the heart. Appropriate control experiments verified that 31P-NMR spectra solely originated from this organ. Acute effects occurring shortly after adriamycin administration are expressed in 31P spectra as a dose-dependent decline in the cardiac levels of phosphocreatine, after which stabilization at a new steady-state level occurs. These acute effects of a single dose are complete in 30-60 min and no significant further changes take place within 150 min after drug introduction. Longer-term effects of single high doses and of multiple lower doses were measured up to a week after the initiation of treatment. It seemed that at a total dose of 20 mg/kg, drug-induced interference with cardiac energy metabolism was more pronounced than at the same dose in the acute phase. These 31P-NMR data demonstrate that adriamycin treatment is accompanied by a decrease of the cardiac phosphocreatine/ATP ratio which might be an expression of the well-established cardiotoxicity of the drug.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Doxorubicin; Energy Metabolism; Heart; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Rats; Rats, Inbred Strains

Hamsters with either the dilated (BIO 53.58) or hypertrophic (BIO 14.6) form of cardiomyopathy and an inbred control strain of hamster (F1B) were treated for 6 months with high-dose L-carnitine (1 g/kg/day i.p.). After treatment, the animals were killed and their hearts perfused by the isolated working technique. Mechanical performance (as indicated by the double product of heart rate and left ventricular [LV] peak systolic pressure) of both carnitine-treated cardiomyopathic groups was increased significantly above their respective sham-treated groups. Associated with these increases in mechanical performance were significant increases in both peak-positive LV dP/dt (index of contractility) and peak negative dP/dt (index of relaxation) in both carnitine-treated myopathic groups. Serum carnitine levels were increased 10-15 times within 2 hours after injection of L-carnitine in all 3 groups. Myocardial free-carnitine levels were increased twofold in both control and dilated myopathic hearts above their respective sham-treated groups, restoring the level in the dilated hearts comparable to those of controls. Myocardial carnitine levels in the hypertrophic group were not significantly affected by treatment. Total high-energy phosphate stores, i.e., ATP plus creatine phosphate, were restored to control levels by L-carnitine treatment in both cardiomyopathic groups. Levels of the breakdown products of ATP were maintained primarily in the more readily convertible adenosine diphosphate and adenosine monophosphate forms in all three treated groups. These changes resulted in significantly higher ratios of (ATP)/(ADP + AMP + adenosine) and (creatine phosphate)/(creatine) in the treated hearts. This is the first study demonstrating that high-dose L-carnitine treatment results in improved cardiac performance and increased myocardial total high-energy phosphate stores in the Syrian hamster model with one of two distinct forms of cardiomyopathy, i.e., dilated or hypertrophic. The mechanisms for these effects of exogenous L-carnitine treatment cannot be totally explained by changes in oxidative energy metabolism.

Topics: Adenine Nucleotides; Animals; Cardiomyopathies; Carnitine; Coenzyme A; Cricetinae; Heart; Hemodynamics; In Vitro Techniques; Male; Mesocricetus; Myocardium; Phosphates; Phosphocreatine; Tissue Distribution

Topics: Adenosine Triphosphatases; Amyloidosis; Biopsy, Needle; Cardiomyopathies; Cardiomyopathy, Hypertrophic; DNA; Echocardiography; Endocardium; Heart Transplantation; Humans; Myocardium; Myosins; Phosphocreatine

Previous studies have suggested that one of the mechanisms of adriamycin (ADR) cardiomyopathy is depletion of high-energy phosphate stores (HEP). To examine this hypothesis, we used 31P nuclear magnetic resonance to assess the adenosine triphosphate-to-phosphocreatine ratio (ATP-to-PCr ratio) in Langendorff-perfused rabbit hearts. Using either an acute (5 days of therapy at 5 mg/kg/day) or chronic model (7 to 10 weeks of therapy at 1.2 or 1.5 mg/kg twice a week), we compared isovolumetric LV systolic pressure, heart rate, ATP-to-PCr ratios, and histologic lesions between the treated and control animals in each model. In the acute model, there was a significant increase in the ATP-to-PCr ratio (P less than 0.02), without significant changes in myocardial function. Despite significant hemodynamic and histologic alterations in the chronic model, compared to controls, we were unable to identify significant differences in ATP-to-PCr ratios. We conclude that there appear to be differences in energy metabolism between the acute cardiotoxicity and the chronic cardiomyopathy of ADR in the rabbit model and the mechanism of the chronic cardiomyopathy from ADR therapy does not appear to be related to progressive impairment of cellular high-energy phosphate metabolism as measured by the ATP-to-PCr ratio.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiomyopathies; Disease Models, Animal; Doxorubicin; Energy Metabolism; Heart Diseases; Heart Rate; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rabbits

Because of its nondestructive nature, topical nuclear magnetic resonance spectroscopy (TMR) was employed for the noninvasive evaluation of congenital cardiomyopathy (CM) in Syrian hamsters (BIO 14.6 strain). In a preliminary study, the size and pulse duration of the surface coil was determined to ensure that the detecting field covered the animal heart. The phosphate metabolite signals of the heart were distinguished from those of organs near the heart. At the cardiac apex, spectroscopically obtained constituent ratios of lipid/water by 1H-TMR and creatine phosphate/ATP by 31P-TMR were less in hamsters with CM than in the age-matched normal control animals, which was in accordance with biochemical analyses performed after killing the animals.

Topics: Adenosine Triphosphate; Animals; Body Water; Cardiomyopathies; Creatine Kinase; Cricetinae; Hydrogen; Lipids; Magnetic Resonance Spectroscopy; Male; Mesocricetus; Myocardium; Phosphocreatine; Phosphorus; Spectrum Analysis

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Female; Glycogen; Isoproterenol; L-Lactate Dehydrogenase; Lactates; Lactic Acid; Male; Myocardium; Perhexiline; Phosphocreatine; Rats

Catecholamines have been shown to produce irreversible contraction band lesions of myocardial cells. However, little is known about the temporal appearance and correlation of the acute form of coagulative myocytolysis with ECG, hemodynamic and biochemical parameters. Groups of adult mongrel dogs were anesthetized with sodium pentobarbital, infused continuously with isoproterenol (2.5 micrograms/kg/min) and killed after periods of 0, 5, 15, 30, or 60 min. There were two predominant myocardial patterns: 'paradiscal' and 'holocytic' contraction band lesions. Either type of lesion was non-existent or rare in the control hearts. The small 'paradiscal' contraction band lesions were present as early as 5 min of isoproterenol infusion, particularly in the inner myocardial layer. The large 'holocytic' contraction band lesions were present by 15 min, however, they were not produced in any significant numbers before 30 min. Both types of contraction band lesions continued to accumulate up to 60 min. ST segment depression was the predominant ECG change. This occurred as early as 5 min when heart rate, blood pressure and dP/dt values had also significantly changed. The high-energy phosphates, phosphocreatine and ATP, started declining as early as 5 min. Furthermore, these phosphates and lactate were distributed in transmural gradients across the left ventricular wall with the greatest change in the endocardial third. This was also the site of the largest accumulation of each type of contraction band lesion. While the lesions correlated with certain biochemical and hemodynamic changes, the underlying pathophysiology is more complex than ischemia or high-energy phosphate depletion alone.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Dogs; Electrocardiography; Female; Glycogen; Hemodynamics; Isoproterenol; Male; Phosphocreatine; Time Factors

The present report is a review of recent experimental studies in a canine model of acute coronary occlusion. The questions addressed were: (1) Does coronary reperfusion reduce myocardial infarct size? (2) What is the relationship between microvascular damage and hemorrhage and the development of myocardial necrosis? (3) What are the biochemical, functional and ultrastructural characteristics of reperfused tissue salvaged from necrosis? Coronary occlusion followed by reperfusion in the dog resulted in significant subepicardial salvage of myocardium if reperfusion was instituted before 6 hours of ischemia. Because ultrastructural evidence of microvascular damage was found only after irreversible damage to myocytes, and because gross hemorrhage after coronary reperfusion was confined to zones of myocardium that were already necrotic, it does not appear that hemorrhage should serve as a deterrent to reperfusing reversibly injured myocytes. Severely ischemic myocardium that had been salvaged by coronary reperfusion required several days before it returned to normal from biochemical, functional and ultrastructural standpoints.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Coronary Circulation; Dogs; Heart; Hemorrhage; Humans; Microcirculation; Myocardial Contraction; Myocardial Infarction; Myocardium; Phosphocreatine

Effects of vitamin E, a fat soluble antioxidant, on the isoproterenol-induced changes in the lipid peroxide activity as determined by a quantitation of malondialdehyde (MDA) content in the myocardium were examined. Isoproterenol treatment (80 mg/kg given over two days in two equal doses) caused more than 100 percent increase in the MDA content which was prevented by pretreatment of the animals with vitamin E (alpha-tocopherol acetate, 10 mg/kg) for two weeks. Animals maintained on vitamin E deficient diet for 8 weeks were found to be more sensitive to isoproterenol-induced increase in the MDA content. A small increase in MDA content was also seen due to vitamin E deficiency alone. These changes were found to be reversible upon a 2 week feeding of the animals on the normal diet coupled with vitamin E treatment. Based on these data it is proposed that free radical mediated increase in lipid peroxide activity may have a role in catecholamine-induced heart disease.

Topics: Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Cardiomyopathies; Catecholamines; Isoproterenol; Lipid Peroxides; Male; Malondialdehyde; Myocardium; Oxygen Consumption; Phosphocreatine; Rats; Rats, Inbred Strains; Vitamin E

Skeletal muscle morphology and mitochondrial oxidative phosphorylation capacity were examined in a family whose members showed very combinations of mental subnormality, cardiomyopathy and muscle weakness. Light and electron microscopic findings suggested a neuropathic process, while tests of mitochondrial function indicated a state of tight coupling of oxidative phosphorylation, a feature in marked contrast to those in biochemical studies so far reported.

Topics: Adenosine Triphosphate; Biopsy; Cardiomyopathies; Electron Transport Complex IV; Female; Humans; Male; Mitochondria, Muscle; Muscles; Muscular Diseases; NADH Dehydrogenase; Oxidative Phosphorylation; Phosphocreatine

Topics: Animals; Aorta, Thoracic; Cardiac Surgical Procedures; Cardiomyopathies; Cyclic AMP; Electric Stimulation; Humans; Levodopa; Mitochondria, Heart; Myocardium; Norepinephrine; Oxygen Consumption; Phosphocreatine; Phosphorus; Rabbits; Rats; Stress, Physiological

Ethimizol in a dose of 10 mg/kg prevents the decrease of calcium and creatine phosphate content in the myocardium of rats exposed to electrical stimulation. The drug was shown to exert a stimulant action on the heart adenyl cyclase system. It is suggested that the action mode of ethimizol on myocardial energy metabolism is connected with an activation of the adenyl cyclase system followed by the increased plasma membrane cell permeability by calcium ions.

Topics: Adenylyl Cyclases; Animals; Calcium; Cardiomyopathies; Cell Membrane Permeability; Energy Metabolism; Etimizol; Imidazoles; Male; Myocardium; Phosphocreatine; Rats

The crucial point in the pathogenesis of isoproterenol-induced myocardial necrotization is an abundant intracellular Ca accumulation leading to high energy phosphate exhaustion. Accordingly, in the early stage of the isoproterenol-induced necrotization process, the onset of ATP and creatine phosphate breakdown strictly parallels the acute Ca gain. In this type of necrosis, the Mg losses from the myocardium appear as a concomitant phenomenon. The hearts can be protected against the deleterious Ca overload and necrotization by increasing the plasma concentration of Mg, K, or H ions in order to counterbalance Ca according to the ration (see article). On the other hand, if Mg, K, or H ion concentrations are too low, isoproterenol-induced Ca uptake and myocardial lesions are potentiated.

Topics: Adenosine Triphosphate; Animals; Calcium; Cardiomyopathies; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Isoproterenol; Magnesium; Myocardium; Necrosis; Phosphocreatine; Potassium; Rats

In the left ventricle of the dog, a transmural difference is present in the normal state for various metabolites and persists in the experimental conditions studied. ATP stores are maintained both in the endo-as well as epicardium at the expense of PC. This is true for systemic hypoxia, hemorrhagic shock, and isoproterenol infusion. In severe ischemia, however, endocardial ATP is lower, while the transmural gradient for PC is increased due to a marked decrease in endocardial PC content. Our studies underline the importance of nonhomogeneity of the left ventricular wall and demonstrate that the subendocardium is more subject to anaerobic metabolism, especially when coronary perfusion pressure is decreased.

Topics: Adenine Nucleotides; Animals; Cardiomyopathies; Coronary Disease; Dogs; Hypoxia; Isoproterenol; Lactates; Mitochondria, Muscle; Myocardium; Phosphocreatine; Shock, Hemorrhagic

Skeletal and heart muscle fibers undergo severe functional and structural alterations, resulting in necrotization as soon as extracellular Ca ions penetrate excessively into the sarcoplasm, so that the capacities of the Ca binding or extrusion processes become insufficient. In mechanically injured skeletal muscle fibers, this necrotization process begins in the neighborhood of the membrane lesion where a large Ca inward transport takes place. Accordingly, elimination of Ca from the Ringer solution or an outward electric current which blocks the influx of extracellular Ca prevents the onset of necrotization, whereas additional Ca or an inward electric current which augments the influx of Ca potentiates the course of degradation. The crucial reaction in the production of necroses in skeletal and heart muscle fibers is a high energy phosphate deficiency which results (a) from excessive activation of Ca-dependent intracellular ATPases, and (b) from Ca-induced mitochondrial destruction. This applies especially to myocardial fiber damage caused by large doses of beta-adrenergic catecholamines such as isoproterenol. The number and size of the isoproterenol-induced cardiac lesions are obviously determined by the extent and, particularly, by the duration of the Ca-mediated high energy phosphate penury. Substances which sensitize the myocardium to catecholamine-induced necrotization (9-alpha-fluorocortisol, dihydrotachysterol, NaH2PO4) act by potentiating intracellular Ca overload and high energy phosphate breakdown. Conversely, verapamil D 600, and other Ca-antagonistic compounds protect the structural integrity of the heart muscle fibers by restricting transmembrane Ca influx and, consequently, ATP and creatine phosphate exhaustion.

Topics: Adenosine Triphosphate; Animals; Calcium; Cardiomyopathies; Heart; Humans; Isoproterenol; Muscles; Necrosis; Phosphocreatine; Rats; Verapamil

The effect of prolonged adminstration of ehtanol on cardiac metabolism, contractility, and ultrastructure was investigated. Dogs received 400 ml of a 25 percent solution of ethanol during a period of 3-6 months. Repeated heart muscle biopsied revealed a significant diminution in the activity of intramitochondrial NAD-linked isocitrate dehydrogenase in the animals exposed to alcohol. Oxidative, phosphorylation of mitochondria was measured polarographically using a vibrating oxygen electrode; respiratory control index and mitochondrial oxygen consumption were markedly reduced (p less than 0.001). Myocardial ATP content was significantly diminished (p less than 0.025). Electron microscopic changes observed consisted of mitochondrial degeneration, dehiscence of intercalated discs, and dilatation of intercellular spaces. The average force velocity curve was shifted downward and to the left in afterloaded contractions with a significant depression of Vmax (p less than 0.01). Both calcium binding and calcium uptake of mitochondria and sarcoplasmic reticulum were inhibited. These results suggest that a disorder in the generation of energy and a defect in calcium binding by subcellular membranes may be the determinant events leading to impaired myocardial function in the course of chronic alcoholism.

Topics: Adenine Nucleotides; Alcoholism; Animals; Binding Sites; Calcium; Cardiomyopathies; Disease Models, Animal; Dogs; Humans; Isocitrate Dehydrogenase; Mitochondria, Muscle; Myocardial Contraction; Myocardium; Oxygen Consumption; Phosphocreatine; Sarcoplasmic Reticulum

Topics: Adenosine Triphosphate; Animals; Calcium; Cardiomyopathies; Dihydrotachysterol; Heart; Hydrocortisone; Isoproterenol; Magnesium; Myocardium; Phosphates; Phosphocreatine; Potassium Chloride; Prenylamine; Rats; Time Factors; Verapamil

Topics: Adrenal Cortex Hormones; Cardiomegaly; Cardiomyopathies; Dermatomyositis; Diagnosis, Differential; Electrocardiography; Female; Humans; Middle Aged; Mitral Valve Insufficiency; Phosphocreatine; Tachycardia

Topics: Aspartate Aminotransferases; Cardiomyopathies; Child; Creatine Kinase; Diphtheria; Diphtheria Toxin; Electron Transport Complex IV; Fructose-Bisphosphate Aldolase; Glucosephosphate Dehydrogenase; Heart Block; Heart Ventricles; Humans; L-Lactate Dehydrogenase; Lactates; Male; Methods; Myocardium; Phosphocreatine

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Cardiomyopathies; Diet; Disease Models, Animal; Heart Failure; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Norepinephrine; Oxygen Consumption; Phosphocreatine; Rabbits; Rats

Topics: Animals; Cardiomyopathies; Glycogen; Hyperthyroidism; Magnesium; Methionine; Myocardium; Phosphocreatine; Rabbits

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Cats; Heart Ventricles; Hypertrophy; In Vitro Techniques; Muscles; Papillary Muscles; Phosphocreatine; Pulmonary Artery

Topics: Adenosine Triphosphate; Animals; Cardiomyopathies; Cats; Heart Ventricles; Hypertrophy; In Vitro Techniques; Muscles; Papillary Muscles; Phosphocreatine; Pulmonary Artery